The Dana-Farber Cancer Institute (DFCI) and consorting components at the Harvard Medical School, Harvard School of Public Health, Children's Hospital Medical Center, and Brigham and Women's Hospital have organized their efforts in basic and clinical research to develop a Specialized Program of Research Excellence (SPORE) in breast cancer. The objectives of this SPORE are to: 1) enhance interactions among existing investigator-initiated breast cancer research efforts; 2) facilitate the development of new experimental breast cancer studies; 3) support the career development of laboratory and clinical investigators in breast cancer; and 4) implement the translation of basic research findings into innovative applied research with patients and populations that will reduce breast cancer morbidity and mortality. The available evidence suggests that cumulative genetic alterations of growth regulatory genes are responsible for progression to invasive carcinoma. This issue will be addressed as a major focus of this SPORE and the development of a molecular genetic model of mammary neoplasia will be translated to the prevention, diagnosis and therapy of breast cancer. Several projects in this program have received partial funding. Dr. Philip Leder will study the interaction of dominant oncogenes and tumor suppressor genes in transgenic breast tumor models. Dr. Judah Folkman will study the role of angiogenesis in progression to invasive cancer. Drs. Graham Colditz will utilize the large cohort of women in the Nurses' Health Study to quantify gradations of risk in premalignant breast lesions, the accumulation of genetic alterations and the effects of epigenetic factors such as hormones. This model will also be translated to the study of women at increased susceptibility for developing breast cancer in the High Risk-Breast Cancer Genetics Program initiated by Drs. Judy Garber and Fred Li. The studies proposed by Drs. Karen Antman, Jeffrey Sklar and Emil Frei III will exploit the presence of genetic alterations in breast cancer cells to screen for occult infiltration of marrow or peripheral blood progenitor cells used in the setting of high dose chemotherapy and autologous stem cell support. The translational research activities of this SPORE have accordingly been organized into three major components: 1) Molecular and Cellular Biology; 2) Etiology and Prevention; and 3) Diagnosis and Therapy. Research and Developmental Projects contribute to each of these components with overall support from two Cores (Tissue Bank and Molecular Biology).